Membrane biogenesis is essential for cell growth and differentiation. During membrane biogenesis in eukaryotic cells, newly synthesized phospholipids must be transported from their sites of synthesis to their sites of function. Vesicular traffic in eukaryotic cells is characterized by two steps of membrane rearrangement, the formation of vesicles from donor membranes and their fusion with acceptor membranes. With respect to vesicle formation, several of the cytosolic proteins implicated in budding and fission have been identified. These proteins stimulate the formation of constitutive secretory vesicles and immature secretory granules from the trans-Golgi network.
Phosphatidylcholine transfer protein (PC-TP) is a member of a diverse set of cytosolic lipid transfer proteins which are distinguished by their ability to transfer phospholipids between membranes in vitro (Wirtz, K. W. A. (1991) Ann. Rev. Biochem. 60:73-99). PC-TPs purified from bovine and rat liver are 213 amino acids in length and have molecular masses of about 28 kDa. The cDNAs which encode full-length bovine PC-TP and fragments of rat and mouse PC-TPs were recently isolated (Geijtenbeek, T. B. H. et al. (1996) Biochem. J. 316:49-55). In adult mice, levels of PC-TP RNA are highest in liver, kidney and testis, lower in lung, heart, and gastrointestinal tissues, and nearly undetectable in brain and thymus. PC-TP RNA is present in all stages of mouse embryo development, which suggests a role for PC-TP in cell growth and differentiation (Geijtenbeek et al., supra).
Pulmonary surfactant is a lipid-rich material that prevents lung collapse by lowering surface tension at the air-liquid interface in the lung alveoli. It is composed primarily of the phospholipids PC and phosphatidylglycerol and lesser amounts of cholesterol and surfactant-associated proteins. Levels of PC-TP in fetal rat lung are greatest just prior to term and parallel the levels of surfactant production and of the enzymes required for PC synthesis (Teerlink, T. et al. (1982) Biochim. Biophys. Acta 713:61-67).
The liver secretes large amounts of PC into the bile. PC-TP is proposed to contribute to PC secretion by transporting PC from its site of synthesis in the endoplasmic reticulum to the inner leaflet of the canalicular membrane, possibly in concert with the class III metabolic P-glycoprotein encoded by the Mdr2 gene (Smit, J. J. M. et al. (1993) Cell 75:451-462; Geijtenbeek et al., supra).
PC-TP may play an essential role in membrane biogenesis by delivering PC to sites of growth. Furthermore, PC-TP may also play a role in the signal transduction pathway by delivering PC from intracellular stores to sites of enzymatic hydrolysis where the PC-specific phospholipases C and D convert PC into lipid mediators such as phosphatidic acid, diacylglyerol and arachidonic acid (Exton, J. H. (1994) Biochim. Biophys. Acta 1212:26-42; Geijtenbeek et al., supra).
Phosphatidylethanotamine (PE) comprises a portion of the lipid pool of many organisms, including bacteria, lower metazoa, fish, amphibia, reptiles, birds, and mammals. PE is synthesized from ethanolamine and diacylglycerol by a number of mitochondrial or endoplasmic reticular enzymes. PE is a source of fatty acid anions and diacylglycerol. Intracellular phospholipase C metabolizes PE to produce diacylglycerol, a component of the protein kinase C-stimulating second messenger pathway. Thus PE is an important intracellular component of the intracellular fatty acid synthesis and of the cell cycle.
Membranes composed of PE and phosphatidylglycerol, such as found in bacteria, are permeabilized by mammalian defensins (Hristova, K. et al. (1997) J. Biol. Chem. 272:24224-24233). Separately, biochemically modified PE may mediate hippocampal long term potentiation and some of the symptoms associated with Sjogren-Larsson syndrome (Pavlinova, L. I. et al. (1997) Neurosci. Behav. Physiol. 27:234-239; James, P. F. and Zoeller, R. A. (1997) J. Biol. Chem. 272:23532-23539).
A number of putative PE-binding proteins (PE-BPs) have been isolated from human, bovine and rat brain during searches for molecules with differing, but specific, biochemical and pharmacological properties (Hori, N. et al. (1994) Gene 140:293-294). The presence of PE-BPs in cytoplasmic and membrane compartments suggested their possible implication in transport or signal mechanisms between membranes and the cytoplasm. Subsequent tissue expression analysis showed that some of these genes are transcribed in various rodent tissues, such as brain, spleen, lung, liver, skeletal muscle, kidney, and testis. PE-BPs have been implicated as essential for normal spermatogenesis in the rat (Seddiqi, N. et al. (1996) Experimentia 52:101-110).
Similar putative PE-BPs have been identified in the parasitic nematode Onchocerca volvulus. Erttmann, K. D. and Gallin, M. Y. (1996; Gene 174:203-207) speculated that the nematode PE-BPs might play a role in odorant response, a process essential in development, feeding, and mating.
The discovery of two new human phospholipid binding proteins and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of disorders associated with fetal development, reproduction, cell proliferation, and the immune response.